The balance of excitation and inhibition in the nervous system appears to be a key factor in the etiology of many neurodegenerative diseases. However, the mechanisms that control this balance are poorly understood. Recent studies suggest that homeostatic mechanisms monitor and regulate the levels of cellular excitation in the nervous system. A model for the homeostatic regulation of neuronal excitability has been developed at a glutamatergic synapse in Drosophila that parallels models of synaptic homeostasis in the vertebrate central and peripheral nervous systems. This proposal details experiments designed to elucidate the properties of synaptic homeostasis in Drosophila. The approach will be twofold. First, electrophysiological techniques will be conducted to characterize the time-course and reversibility of synaptic homeostasis. To do this, the GAL4-UAS system will be used, which will allow conditional disruption of muscle excitation, and therefore, conditional activation of homeostatic signaling. Second, a genome-scale, reverse genetics screen to identify genes involved in homeostatic signaling will be performed. To conduct this screen, a library of 7260 Drosophila dsRNA molecules is available.